Loss of progesterone receptor links to high proliferation and increases from primary to metastatic endometrial cancer lesions

Ingvild Løberg Tangen, Henrica M.J. Werner, Anna Berg, Mari K. Halle, Kanthida Kusonmano, Jone Trovik, Erling A. Hoivik, Gordon B. Mills, Camilla Krakstad, Helga B. Salvesen

    Research output: Contribution to journalArticle

    43 Scopus citations

    Abstract

    Objective In endometrial cancer loss of progesterone receptor (PR, gene name PGR) is associated with aggressive disease and altered response to hormonal treatment. The aim of this study was to investigate changes in PR expression level with disease progression, and explore whether differences in gene expression according to PR status can be linked to processes involved in cancer development elucidating new therapeutic opportunities. Methods 686 primary endometrial cancers and 171 metastatic lesions were investigated for PR expression in relation to clinical and histopathological data. Protein levels were investigated by immunohistochemistry and reverse phase protein array, and mRNA levels by DNA oligonucleotide microarray. Results PR protein level was significantly associated with PGR mRNA expression (P < 0.001) and patient survival (P < 0.001). Loss of PR increased with disease progression, with 23% of the primary tumours and 76% of metastases demonstrating PR loss. Using a cell cycle progression signature score, PR loss was associated with increased proliferation for both oestrogen receptor (ER) positive and negative tumours. Through a Connectivity Map search, CDK inhibitors and other drugs with anti-proliferative effects were suggested in particular for treatment of patients with loss of PR. Conclusion Loss of PR in endometrial cancer is associated with increased proliferation, poor survival, and increases from primary to metastatic lesions. Based on expression profiles, CDK inhibitors may have activity in PR negative tumours, supporting further testing in clinical trials for patients with systemic endometrial cancer dependent on PR status.

    Original languageEnglish (US)
    Pages (from-to)3003-3010
    Number of pages8
    JournalEuropean Journal of Cancer
    Volume50
    Issue number17
    DOIs
    StatePublished - Nov 2014

    Keywords

    • CDK inhibitors
    • Endometrial cancer
    • Progesterone receptor
    • Survival

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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    Tangen, I. L., Werner, H. M. J., Berg, A., Halle, M. K., Kusonmano, K., Trovik, J., Hoivik, E. A., Mills, G. B., Krakstad, C., & Salvesen, H. B. (2014). Loss of progesterone receptor links to high proliferation and increases from primary to metastatic endometrial cancer lesions. European Journal of Cancer, 50(17), 3003-3010. https://doi.org/10.1016/j.ejca.2014.09.003